The present invention describes submicron dispersions in water of ordinarily poorly-water-soluble organic substances. For instance, in practice of drug therapy there is a recognized need for ways to deliver water-insoluble pharmaceuticals in a stable liquid form suitable for intravenous, inhalation or other non-topical administrations. This need has been previously addressed in a number of ways including incorporation of the water-insoluble drug into micelles, delivery of suspensions of microspheres containing the drug, emulsification of the drug with oils and the use of concentrated solutions of water-soluble polymers. The same problems exist with any water-insoluble organic substances, such as pigments for staining fabrics or ink preparations.
By way of example, in the preparation of pharmaceutical formulations, the addition of surface-active agents or surfactants to an aqueous solution is used to form water soluble aggregates called micelles. These micelles contain two regions of interest a "hydrophobic core" and a hydrophilic outer shell. Compounds that are poorly soluble in water, but soluble in organic solvents can be dissolved inside the hydrophobic core of these micelles and thereby brought homogeneously into an overall aqueous medium. An example of this type of pharmaceutical formulation is the incorporation of the antifungal antibiotic Amphotericin B into micelles with the use of bile acid. Janknegt et. al., 23 Clin. Pharm. 279 (1992). Formulation of Amphotericin B in the micelles of deoxycholic acid is marketed for parenteral use under the name Fungizone.
A similar approach is to dissolve the drug in a vehicle which contains a concentrated solution of an amphipathic compound. Amphipathic compounds have both a hydrophobic and a hydrophilic region as part of their structure. Micelles will also be formed with the use of these compounds. On example of this type of formulation is the preparation of Cyclosporin A, an water-insoluble immunosuppressive agent used to prolong the survival of allogeneic transplants. Cyclosporin A is dissolved in Cremophor and 32.9% (w/v) of alcohol. Cremophor is a polyoxyethylated castor oil. This solution is further diluted in 0.9% sodium chloride or 5% dextrose for intravenous administration. This formulation of Cyclosporin A is marketed under the name Sandimmune IV by Sandoz Pharmaceutical Corporation.
Another way of formulating water-insoluble pharmaceuticals is to incorporate the drug into a microsphere containing a biodegradable polymer. The drug is dissolved in an organic solvent such as methylene chloride and mixed with a biodegradable polymer which is also dissolved in the organic solvent. An aqueous medium is then added to this mixture and vigorously mixed to form an emulsion. The addition of the aqueous solution causes the biodegradable polymer to precipitate. The organic solvent is then evaporated from the mixture. When the organic solvent is evaporated, solid microspheres are left behind. The microspheres are then lyophilized and can be resuspended by the addition of another aqueous solution.
Water-insoluble pharmaceuticals can also be incorporated into oil/water microemulsions to be administered parenterally. Levy et al., 54 Int. J. Pharm. 103 (1989). Water-insoluble organic compounds have been suspended in organic solution through a process of infusion of an aqueous precipitating liquid into an organic solvent solution which contains the organic substance of interest. EP 0 169 618 B2 (Nov. 10, 1993). Furthermore, water-insoluble organics have been suspended in gelatin or collagen. Wunderlich et. al., WO 93 10,768 (Jun. 10, 1993). However, gelatin is inherently hydrophilic and the disclosure requires that the resulting particle be electrically neutral so as to enhance oral adsorption. The particle will therefore be hydrophobic in this neutral state. The present invention, due to a net charge in the final product, has improved solubility, biodistribution and kinetics.
All of the above mentioned known approaches to delivering water-insoluble pharmaceuticals have one common disadvantage to their use. The presence of substantial amounts of surfactant, water soluble polymer, amphipathic compounds etc., in the delivery vehicle can cause vehicle-associated toxicity. The use of Cremophor in the formulation of Cyclosporin A (Sandimmune IV) has been shown to cause anaphylactoid reactions (19 Intell. Clin. Pharm. 425 (1985)) and the use of surfactants like bile acids for the delivery of Amphotericin B is known to cause the lysis of red blood cells (Forster and Davis, 40 J. Pharm. Pharmacol. 325 (1988)) and increased nephrotoxicity (Inselman et. al., 14 Renal Failure 17 (1992)).
Any method that improves the delivery of water-insoluble pharmaceuticals such that the risk of vehicle-associated side effects is reduced would be of great value to the medical community. The purpose of this invention is to show that the amount of stabilizing and/or solubilizing vehicle of a water-insoluble pharmaceutical can be reduced and still be able to be properly delivered thereby lower the risk of vehicle-associated side effects caused by the current formulations.